Forxiga (dapagliflozin) for Treatment of Type 2 Diabetes

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Forxiga (dapagliflozin) is a type 2 diabetes drug jointly developed by AstraZeneca and Bristol-Myers Squibb (BMS). It is the first SGLT2 (sodium / glucose cotransporter 2) class drug developed by BMS and AstraZeneca.

In November 2012, Forxiga was granted marketing approval by the European Commission (EC) for the treatment of type 2 diabetes in Europe. The drug is also being reviewed for approval in many countries across the world. It has received marketing approval in more than 40 countries across the world including Australia, Brazil, Mexico, and New Zealand.

AstraZeneca and BMS received approval from the US Food and Drug Administration (FDA) for dapagliflozin as a once-daily oral treatment for adults with type 2 diabetes mellitus in January 2014. The drug will be marketed in the US under the brand name Farxiga.

Type 2 diabetes symptoms and occurrence

Type 2 diabetes is a metabolic disorder that is characterised by high levels of sugar in the blood. The symptoms of the disease include frequent urination, constant appetite and excess thirst. These symptoms are found in about 85% to 95% of adult patients diagnosed with diabetes.

It was reported that about 53 million people across Europe were affected by type 2 diabetes in 2011. The disease is expected to affect about 64 million in Europe by 2030.

Dapagliflozin’s mechanism of action

Forxiga contains sodium-glucose cotransporter (SGLT) 2 inhibitor. The drug works in the kidney by removing the extra glucose present in urine. It also helps in reducing the blood sugar levels, weight as well as blood pressure. It does not contain any insulin, meaning can be used as an add-on treatment option.

The drug is available in 5mg and 10mg doses for oral administration.

Clinical trials on forxiga (dapagliflozin)

BMS and AstraZeneca conducted a Phase I clinical trial on Forxiga between February 2009 and March 2009. It was an open-label, randomised and pharmacokinetics study which enrolled 24 patients with type 2 diabetes. The primary outcome measure of the study was finding the exposure to the investigational drug. The secondary outcome measures included the assessment of the safety and tolerability and effects of the drug.

BMS evaluated Forxiga in the Phase II clinical trial that was conducted between April 2009 and August 2010. It was a randomised, double-blind, placebo-controlled and parallel-group study, which enrolled over 44 patients. The primary outcome measure of the study was finding the insulin sensitivity in 12 weeks. The secondary outcome measures included finding the insulin secretion after 12 weeks of the study.

The EU approval for Forxiga was based on data received from 11 Phase III clinical trials conducted jointly by BMS and AstraZeneca. The randomised, double-blind and placebo-controlled studies enrolled over 5,693 patients with type 2 diabetes internationally. The studies assessed the safety and efficacy of Forxiga in comparison with placebo. The subjects were administered 10mg of the drug once daily as oral therapy.

Phase III studies met the endpoint of achieving HbA1c < 7%. The results also showed that Forxiga reduced body weight as well as blood pressure. The adverse events found during the clinical studies included an increase in blood creatinine, nausea, rash and dizziness.

The FDA approval for Farxiga was based on monotherapy and combination studies. The studies evaluated Farxiga in combination with metformin, pioglitazone, glimepiride, sitagliptin, or insulin.

It included a 24-week clinical study that enrolled 840 type 2 diabetes patients. The results of the study demonstrated that patients treated with Farxiga 5mg or 10mg doses showed significant reductions in HbA1c of 0.7% and 0.8%, respectively, when compared to placebo plus metformin which showed reductions of just -0.3%.

The combination treatment studies also showed that patients administered with Farxiga 10mg plus metformin XR witnessed statistically significant improvements in HbA1c and FPG compared to monotherapy treatments. A statistically significant reduction in body weight was also observed compared to metformin XR alone.

AstraZeneca and BMS jointly initiated a clinical called DECLARE in April 2013. It is a randomised, placebo-controlled study that will enrol over 17,000 adult patients with type 2 diabetes. It will determine the effect of Farxiga, when added to the patients’ current anti-diabetes therapy, on the risk of cardiovascular (CV) events, such as CV death, myocardial infarction or ischaemic stroke, in comparison with placebo. The study is expected to be completed by 2019.

Marketing Forxiga in Europe and worldwide

In January 2007, BMS and AstraZeneca entered into an agreement to jointly undertake research, development and commercialisation of investigational drugs for diabetes.

In August 2012, BMS purchased Amylin, a US-based pharmaceutical company, for $5.3bn. The acquisition helped BMS and AstraZeneca to stretch the partnership of developing Amylin diabetic drugs including Byetta and Bydureon. Both the companies plan to expand the diabetic drug market operations to the US and other countries across the world by the end of 2013.

BMS and AstraZeneca had earlier developed an antidiabetic agent called Saxagliptin. Other medications approved for the treatment of diabetes include vildagliptin developed by Novartis and sitagliptin produced by Merck.